Many growth factors function by binding receptors with intrinsic tyrosine kinase activity. Signaling by such receptors involves a series of intermediates characterized by SH2 domains that bind tyrosine phosphorylated receptors by a direct interaction between the SH2 domain and specific phospho-tyrosine-containing receptor sequences. GRB7, a SH2 domain protein, has a single SH2 domain at its C-terminal, a central region with similarity to Ras GAP and a proline-rich N-terminus. A related SH2 domain-containing protein, GRB10, exhibits a high degree of homology with GRB7. GRB10 undergoes serine but not tyrosine phosphorylation in response to EGF treatment, but appears to bind to the EGF receptor poorly. An additional member of the GRB7 family, designated GRB14, contains a Pleckstrin homology domain in its central region and a carboxy-terminal SH2 domain. GRB14 mRNA is expressed at high levels in a broad range of tissues including liver, kidney, pancreas, testis, ovary, heart and skeletal muscle. Expression of the GRB14 protein in breast carcinomas is strongly correlated with estrogen receptor positivity.